Smita Kulkarni, Ph.D.

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Research Focus

Dr. Kulkarni works on discovering variation in non-coding regions of the genome and their relevance to human health and disease.

She is particularly interested in the role of common genetic variation in HIV disease. Here, she tries to decipher why the clinical outcome of HIV-1 infection is highly variable, i.e. why a small number of individuals with HIV does not develop typical clinical symptoms of the disease and is less likely to transmit HIV to others.

Dr. Kulkarni has over 8 years of expertise in the field of immunogenetics, specifically gene regulation, and works on the development of new methodologies.

Inside the Lab

Several genetic factors can modulate HIV-1 disease. However, genome-wide association studies (GWAS) across populations have shown that some of the identified disease-associated single nucleotide polymorphisms are in non-coding regions. Due to lack of functional explanation of the observed associations, these host genetic factors cannot be currently utilized as vaccine or drug targets. We are interested in studying non-coding gene variation that modulates HIV-1 disease.

Effect of lncRNA on HIV disease. Less than 3% of the entire transcriptome is protein coding, signifying that non-coding RNAs represent most of the human transcriptome. Long non-coding RNA transcripts, termed lncRNAs (>200bp) have been identified in mammalian genomes by analysis of transcriptomic data, and while thousands of lncRNAs are known, not many of their functions have been identified. The lincRNAs have been implicated in the regulation of many cellular and developmental processes such as imprinting, dosage compensation, cell cycle regulation, pluripotency, retrotransposon silencing, meiotic entry, and telomere lengthening. My lab is interested in the role of lncRNAs in HIV replication and latency.

We have identified polymorphisms in the lncRNA genes that associate with HIV viral load control. These lncRNAs could potentially affect HIV pathogenesis and could represent the first example of a variation in lncRNA expression that affects disease; we are further investigating the function of inter-genic loci that mark diversity in disease outcomes.

Role of alternative 3’UTRs in gene regulation and diseases. Several human genes utilize alternative polyadenylation to generate transcript isoforms with varying lengths of 3’untranslated regions (3’UTR). 3’UTRs encode docking sites for regulatory RNA binding proteins and microRNAs, and thus are major determinants of post-transcriptional gene regulation. Alternative 3’UTR usage is extensively modulated in development, differentiation, proliferation, and neuron activation; alternative 3’UTRs could contribute to both gene expression and protein diversity.

Mutations in polyadenylation signals and other poly(A) cis-elements that lead to changes in gene expression can contribute to the development of human genetic diseases. A dysregulation of alternative 3’UTRs plays a role in cardiac hypertrophy and tumor progression. Manipulation of the length of 3’UTR can alter gene regulation and is considered promising for future therapeutic blocking of angiogenic signals in tumors.

Even though over 70% of human genes contain multiple poly(A) sites and could potentially be subjected to alternative 3’UTR regulation, it is not known what percentage is actually regulated by alternative 3’UTR and whether this results in any biological effects. We are studying alternative 3’UTRs of immune genes that may have an effect on immune response diversity and subsequent outcomes of infectious and autoimmune diseases.